The Narcotic Drug and Opioid Peptide Basic Research Project enters its 30th year with continued vigor and enthusiasm. Several aspects of the Project are logical extensions of efforts of earlier years; other aspects represent entirely new areas of interest. Included in the former category are studies that continue to refine and analyze the pharmacological effects of opioids in the rhesus monkey. Our research on the analgesic, respiratory depressant, and reinforcing effects of opioids will continue, using established methods. In addition, studies using newly developed analgesia assays are included that may provide evidence for novel, additional pathways through which opioids can provide therapeutic action against pain and inflammatory processes. Similarly, traditional studies of the reinforcing effects of opioids will be supplemented by new procedures that may provide evidence for changes in the reinforcing effects of opioids during withdrawal and protracted withdrawal. The drug discovery program will continue to evaluate the in vivo and in vitro effects of opioids in rodents and in vivo effects of opioids in non-human primates. The goal of this effort is to identify novel pharmacotherapies for opioid abuse, and new therapeutic indications for opioid drugs. We currently are evaluating microencapsulated buprenorphine as a potential pharmacotherapy, and delta agonists as potential antidepressant agents. The work of the human behavioral pharmacology laboratory, set up in the prior renewal, continues with the focus on evaluation of buprenorphine as a pharmacotherapy for opioid abuse. Studies using labeled carfentanil in PET imaging studies will compare buprenorphine's binding to central mu-opioid receptors with its antagonism of hydromorphone's pharmacological effects. Two of the areas of study are new. One is an initial evaluation of opioid-endocrine interactions, particularly the interaction between opioids and the hypothalamic-pituitary-adrenal axis (HPA). In addition to evaluation of the acute effects of mu and kappa opioids on the HPA axis in primates, this area of research will exploit earlier studies in rodents that indicated that stress and measures of the HPA axis activity may reveal an extended withdrawal syndrome. We plan to take this finding to the primate in respiration and drug self-administration assays. The second new area of investigation is a major chemical venture that has as its goal the development of radiolabeled ligands specific to opioid function in pharmacological, physiological, and pathophysiological conditions in animals and humans.